2.7 Which HDAC to Inhibit in Asthma?
Trichostatin A (TSA, Fig. 2) has originally been reported as a fungistatic antibiotic
and is one of the first natural compounds found to inhibit HDACs. This nonselective
HDACi has been evaluated in allergen-induced airway inflammation. TSA significantly reduced airway hyperresponsiveness in both acute and chronic asthma models
at concentrations of 1, 2, and 5 mg/kg [64–66]. Additionally, the number of
eosinophils and the expression of IL-4 and IL-5 were decreased in bronchoalveolar
lavage fluid upon treatment with 1 mg/kg TSA. The anti-inflammatory effects of
TSA may partly be the result of enhanced apoptosis in eosinophils and neutrophils
through a caspase-activating pathway, not involving PI3K nor NF-κB [67].
At a lower concentration, namely, 0.6 mg/kg, TSA did not reduce airway
inflammation, but it did inhibit airway hyperresponsiveness [68]. This could be
explained by blockage of airway smooth muscle contraction by TSA, even at
lower concentrations, by decreasing the release of Ca
2+ from the sarcoplasmic
reticulum. A specific HDAC might be involved in this pathway, possibly HDAC8.
This HDAC is known to deacetylate cortactin, which subsequently promotes actin
filament polymerization and smooth muscle contraction and therefore plays an
important role in the regulation of cytoskeletal dynamics of airway smooth muscle
(Fig. 1c) [68–70]. In contradiction, inhibition of HDAC8 has been shown to increase
Ca
2+
flux and subsequent apoptosis in T cells by activating PLCG1 [71]. In any case,
treatment with the HDAC8-selective inhibitor PCI-34051 (Fig. 2) showed that
inhibition of HDAC8 alone attenuates airway hyperresponsiveness, airway inflammation, and to some extent even airway remodeling [72]. In view of airway
remodeling, HDAC6 should also be considered as a target since its main function
is to deacetylate α-tubulin [73, 74]. Reversible acetylation of α-tubulin regulates
microtubule stability and function, with acetylation marking stabilized microtubules
and an associated decrease in cellular motility (Fig. 1d). In asthma, inhibition of
HDAC6 potentially maintains the cellular morphology of airway smooth muscle
cells and thus may prevent airway remodeling. Although administration of the
HDAC6-selective inhibitor tubastatin A (Fig. 2) in asthmatic mice reduced inflammation and airway hyperresponsiveness to a lesser extent than the HDAC8 inhibitor,
it was similarly involved in decreasing α-smooth muscle actin and TGF-β1, both
markers of airway remodeling [72]. In summary, inhibition of HDAC6 and HDAC8
might relieve airway constriction and prevent airway remodeling.
From a theoretical standpoint, inhibiting all HDACs, like TSA does, will lead to
conflicting effects, but in reality a mostly positive outcome on inflammation and
airway hyperresponsiveness is observed in asthma. This is especially fascinating
given the fact that it was administered systemically by either subcutaneous or
intraperitoneal injection. Although TSA did not seem to be toxic or induce noticeable side effects during the duration of the experiments, respiratory diseases are
ideally treated by local administration to reduce the chance of systemic side effects.
Since HDACs are ubiquitously expressed, this may offer substantial benefits to
treatment with HDACi in airway diseases.
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
439
Trichostatin A (TSA, Fig. 2) has originally been reported as a fungistatic antibiotic
and is one of the first natural compounds found to inhibit HDACs. This nonselective
HDACi has been evaluated in allergen-induced airway inflammation. TSA significantly reduced airway hyperresponsiveness in both acute and chronic asthma models
at concentrations of 1, 2, and 5 mg/kg [64–66]. Additionally, the number of
eosinophils and the expression of IL-4 and IL-5 were decreased in bronchoalveolar
lavage fluid upon treatment with 1 mg/kg TSA. The anti-inflammatory effects of
TSA may partly be the result of enhanced apoptosis in eosinophils and neutrophils
through a caspase-activating pathway, not involving PI3K nor NF-κB [67].
At a lower concentration, namely, 0.6 mg/kg, TSA did not reduce airway
inflammation, but it did inhibit airway hyperresponsiveness [68]. This could be
explained by blockage of airway smooth muscle contraction by TSA, even at
lower concentrations, by decreasing the release of Ca
2+ from the sarcoplasmic
reticulum. A specific HDAC might be involved in this pathway, possibly HDAC8.
This HDAC is known to deacetylate cortactin, which subsequently promotes actin
filament polymerization and smooth muscle contraction and therefore plays an
important role in the regulation of cytoskeletal dynamics of airway smooth muscle
(Fig. 1c) [68–70]. In contradiction, inhibition of HDAC8 has been shown to increase
Ca
2+
flux and subsequent apoptosis in T cells by activating PLCG1 [71]. In any case,
treatment with the HDAC8-selective inhibitor PCI-34051 (Fig. 2) showed that
inhibition of HDAC8 alone attenuates airway hyperresponsiveness, airway inflammation, and to some extent even airway remodeling [72]. In view of airway
remodeling, HDAC6 should also be considered as a target since its main function
is to deacetylate α-tubulin [73, 74]. Reversible acetylation of α-tubulin regulates
microtubule stability and function, with acetylation marking stabilized microtubules
and an associated decrease in cellular motility (Fig. 1d). In asthma, inhibition of
HDAC6 potentially maintains the cellular morphology of airway smooth muscle
cells and thus may prevent airway remodeling. Although administration of the
HDAC6-selective inhibitor tubastatin A (Fig. 2) in asthmatic mice reduced inflammation and airway hyperresponsiveness to a lesser extent than the HDAC8 inhibitor,
it was similarly involved in decreasing α-smooth muscle actin and TGF-β1, both
markers of airway remodeling [72]. In summary, inhibition of HDAC6 and HDAC8
might relieve airway constriction and prevent airway remodeling.
From a theoretical standpoint, inhibiting all HDACs, like TSA does, will lead to
conflicting effects, but in reality a mostly positive outcome on inflammation and
airway hyperresponsiveness is observed in asthma. This is especially fascinating
given the fact that it was administered systemically by either subcutaneous or
intraperitoneal injection. Although TSA did not seem to be toxic or induce noticeable side effects during the duration of the experiments, respiratory diseases are
ideally treated by local administration to reduce the chance of systemic side effects.
Since HDACs are ubiquitously expressed, this may offer substantial benefits to
treatment with HDACi in airway diseases.
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
439